Mechanistic Modeling of the Relative Biological Effectiveness of Boron Neutron Capture Therapy.

Accurate dosimetry and determination of the biological effectiveness of boron neutron capture therapy (BNCT) is challenging because of the mix of different types and energies of radiation at the cellular and subcellular levels. In this paper, we present a computational, multiscale system of models to better assess the relative biological effectiveness (RBE) and compound biological effectiveness (CBE) of several neutron sources as applied to BNCT using boronophenylalanine (BPA) and a potential monoclonal antibody (mAb) that targets HER-2-positive cells with Trastuzumab. The multiscale model is tested against published in vitro and in vivo measurements of cell survival with and without boron. The combined dosimetric and radiobiological model includes an analytical formulation that accounts for the type of neutron source, the tissue- or cancer-specific dose-response characteristics, and the microdistribution of boron. Tests of the model against results from published experiments with and without boron show good agreement between modeled and experimentally determined cell survival for neutrons alone and in combination with boron. The system of models developed in this work is potentially useful as an aid for the optimization and individualization of BNCT for HER-2-positive cancers, as well as other cancers, that can be targeted with mAb or a conventional BPA compound.

Dosimetric characteristics of the University of Washington Clinical Neutron Therapy System.

The University of Washington (UW) Clinical Neutron Therapy System (CNTS), which generates high linear energy transfer fast neutrons through interactions of 50.5 MeV protons incident on a Be target, has depth-dose characteristics similar to 6 MV x-rays. In contrast to the fixed beam angles and primitive blocking used in early clinical trials of neutron therapy, the CNTS has a gantry with a full 360° of rotation, internal wedges, and a multi-leaf collimator (MLC). Since October of 1984, over 3178 patients have received conformal neutron therapy treatments using the UW CNTS. In this work, the physical and dosimetric characteristics of the CNTS are documented through comparisons of measurements and Monte Carlo simulations. A high resolution computed tomography scan of the model 17 ionization chamber (IC-17) has also been used to improve the accuracy of simulations of the absolute calibration geometry. The response of the IC-17 approximates well the kinetic energy released per unit mass (KERMA) in water for neutrons and photons for energies from a few tens of keV up to about 20 MeV. Above 20 MeV, the simulated model 17 ion chamber response is 20%-30% higher than the neutron KERMA in water. For CNTS neutrons, simulated on- and off-axis output factors in water match measured values within ~2% ± 2% for rectangular and irregularly shaped field with equivalent square areas ranging in a side dimension from 2.8 cm to 30.7 cm. Wedge factors vary by less than 1.9% of the measured dose in water for clinically relevant field sizes. Simulated tissue maximum ratios in water match measured values within 3.3% at depths up to 20 cm. Although the absorbed dose for water and adipose tissue are within 2% at a depth of 1.7 cm, the absorbed dose in muscle and bone can be as much as 12 to 40% lower than the absorbed dose in water. The reported studies are significant from a historical perspective and as additional validation of a new tool for patient quality assurance and as an aid in ongoing efforts to clinically implement advanced treatment techniques, such as intensity modulated neutron therapy, at the UW.

DNA double strand break (DSB) induction and cell survival in iodine-enhanced computed tomography (CT).

A multi-scale Monte Carlo model is proposed to assess the dosimetric and biological impact of iodine-based contrast agents commonly used in computed tomography. As presented, the model integrates the general purpose MCNP6 code system for larger-scale radiation transport and dose assessment with the Monte Carlo damage simulation to determine the sub-cellular characteristics and spatial distribution of initial DNA damage. The repair-misrepair-fixation model is then used to relate DNA double strand break (DSB) induction to reproductive cell death. Comparisons of measured and modeled changes in reproductive cell survival for ultrasoft characteristic k-shell x-rays (0.25-4.55 keV) up to orthovoltage (200-500 kVp) x-rays indicate that the relative biological effectiveness (RBE) for DSB induction is within a few percent of the RBE for cell survival. Because of the very short range of secondary electrons produced by low energy x-ray interactions with contrast agents, the concentration and subcellular distribution of iodine within and near cellular targets have a significant impact on the estimated absorbed dose and number of DSB produced in the cell nucleus. For some plausible models of the cell-level distribution of contrast agent, the model predicts an increase in RBE-weighted dose (RWD) for the endpoint of DSB induction of 1.22-1.40 for a 5-10 mg ml-1 iodine concentration in blood compared to an RWD increase of 1.07 ± 0.19 from a recent clinical trial. The modeled RWD of 2.58 ± 0.03 is also in good agreement with the measured RWD of 2.3 ± 0.5 for an iodine concentration of 50 mg ml-1 relative to no iodine. The good agreement between modeled and measured DSB and cell survival estimates provides some confidence that the presented model can be used to accurately assess biological dose for other concentrations of the same or different contrast agents.

MCNP6 model of the University of Washington clinical neutron therapy system (CNTS).

A MCNP6 dosimetry model is presented for the Clinical Neutron Therapy System (CNTS) at the University of Washington. In the CNTS, fast neutrons are generated by a 50.5 MeV proton beam incident on a 10.5 mm thick Be target. The production, scattering and absorption of neutrons, photons, and other particles are explicitly tracked throughout the key components of the CNTS, including the target, primary collimator, flattening filter, monitor unit ionization chamber, and multi-leaf collimator. Simulations of the open field tissue maximum ratio (TMR), percentage depth dose profiles, and lateral dose profiles in a 40 cm × 40 cm × 40 cm water phantom are in good agreement with ionization chamber measurements. For a nominal 10 × 10 field, the measured and calculated TMR values for depths of 1.5 cm, 5 cm, 10 cm, and 20 cm (compared to the dose at 1.7 cm) are within 0.22%, 2.23%, 4.30%, and 6.27%, respectively. For the three field sizes studied, 2.8 cm × 2.8 cm, 10.4 cm × 10.3 cm, and 28.8 cm × 28.8 cm, a gamma test comparing the measured and simulated percent depth dose curves have pass rates of 96.4%, 100.0%, and 78.6% (depth from 1.5 to 15 cm), respectively, using a 3% or 3 mm agreement criterion. At a representative depth of 10 cm, simulated lateral dose profiles have in-field (⩾ 10% of central axis dose) pass rates of 89.7% (2.8 cm × 2.8 cm), 89.6% (10.4 cm × 10.3 cm), and 100.0% (28.8 cm × 28.8 cm) using a 3% and 3 mm criterion. The MCNP6 model of the CNTS meets the minimum requirements for use as a quality assurance tool for treatment planning and provides useful insights and information to aid in the advancement of fast neutron therapy.

Rapid MCNP simulation of DNA double strand break (DSB) relative biological effectiveness (RBE) for photons, neutrons, and light ions.

To account for particle interactions in the extracellular (physical) environment, information from the cell-level Monte Carlo damage simulation (MCDS) for DNA double strand break (DSB) induction has been integrated into the general purpose Monte Carlo N-particle (MCNP) radiation transport code system. The effort to integrate these models is motivated by the need for a computationally efficient model to accurately predict particle relative biological effectiveness (RBE) in cell cultures and in vivo. To illustrate the approach and highlight the impact of the larger scale physical environment (e.g. establishing charged particle equilibrium), we examined the RBE for DSB induction (RBEDSB) of x-rays, (137)Cs γ-rays, neutrons and light ions relative to γ-rays from (60)Co in monolayer cell cultures at various depths in water. Under normoxic conditions, we found that (137)Cs γ-rays are about 1.7% more effective at creating DSB than γ-rays from (60)Co (RBEDSB = 1.017) whereas 60-250 kV x-rays are 1.1 to 1.25 times more efficient at creating DSB than (60)Co. Under anoxic conditions, kV x-rays may have an RBEDSB up to 1.51 times as large as (60)Co γ-rays. Fission neutrons passing through monolayer cell cultures have an RBEDSB that ranges from 2.6 to 3.0 in normoxic cells, but may be as large as 9.93 for anoxic cells. For proton pencil beams, Monte Carlo simulations suggest an RBEDSB of about 1.2 at the tip of the Bragg peak and up to 1.6 a few mm beyond the Bragg peak. Bragg peak RBEDSB increases with decreasing oxygen concentration, which may create opportunities to apply proton dose painting to help address tumor hypoxia. Modeling of the particle RBE for DSB induction across multiple physical and biological scales has the potential to aid in the interpretation of laboratory experiments and provide useful information to advance the safety and effectiveness of hadron therapy in the treatment of cancer.

Hepatic structural dosimetry in (90)Y microsphere treatment: a Monte Carlo modeling approach based on lobular microanatomy.

UNLABELLED: Selective internal radiation treatment (SIRT) via intrahepatic arterial administration of (90)Y microspheres is an effective therapeutic modality. The conventional and generally applied MIRD schema is based on the premise that the distribution of microspheres in the liver parenchyma is uniform. In reality, however, the distribution of the microspheres follows a distinct pattern, requiring that a model be developed to more appropriately estimate radiation absorbed doses to the different structural/functional elements of the hepatic microanatomy. METHODS: A systematic investigation was performed encompassing a conventional average absorbed dose assessment, a compartmental macrodosimetric approach that accounts for the anticipated higher tumor-to-normal liver activity concentration ratio, dose point-kernel convolution-derived estimates, and Monte Carlo dose estimates employing a spherical and 3-dimensional hexagonal liver model, including various subunits of the hepatic anatomy, down to the micrometer level. RESULTS: Detailed specifics of the radiation dose deposition of (90)Y microspheres demonstrated a rapid decrease in absorbed dose in and around the portal tracts where the microspheres are deposited. The model also demonstrated that the hepatocellular parenchymal and central vein doses could be at significant levels because of a cross-fire effect. CONCLUSION: The reported microstructural dosimetry models can help in the detailed assessment of the dose distributions in the hepatic functional subunits and in relating these doses to their effects. These models have also revealed that the there is a consistent relationship between the average liver dose as calculated by MIRD macrodosimetry and the structural dosimetry estimates in support of the clinical utility of the MIRD methodology. This relationship could be used to more realistically assess patterns of hepatic toxicity associated with the (90)Y SIRT treatment.

Numerical assessment of radiation binary targeted therapy for HER-2 positive breast cancers: advanced calculations and radiation dosimetry.

In our previous publication (Mundy et al 2006 Phys. Med. Biol. 51 1377) we have described the theoretical assessment of our novel approach in radiation binary targeted therapy for HER-2 positive breast cancers and summarized the future directions in this area of research. In this paper we advanced the numerical analysis to show the detailed radiation dose distribution for various neutron sources in combination with the required boron concentration and allowed radiation skin doses. We once again proved the feasibility of the concept and will use these data and conclusions to start with the experimental verifications.

Radiation binary targeted therapy for HER-2 positive breast cancers: assumptions, theoretical assessment and future directions.

A novel radiation targeted therapy is investigated for HER-2 positive breast cancers. The proposed concept combines two known approaches, but never used together for the treatment of advanced, relapsed or metastasized HER-2 positive breast cancers. The proposed radiation binary targeted concept is based on the anti HER-2 monoclonal antibodies (MABs) that would be used as vehicles to transport the nontoxic agent to cancer cells. The anti HER-2 MABs have been successful in targeting HER-2 positive breast cancers with high affinity. The proposed concept would utilize a neutral nontoxic boron-10 predicting that anti HER-2 MABs would assure its selective delivery to cancer cells. MABs against HER-2 have been a widely researched strategy in the clinical setting. The most promising antibody is Trastuzumab (Herceptin). Targeting HER-2 with the MAB Trastuzumab has been proven to be a successful strategy in inducing tumour regression and improving patient survival. Unfortunately, these tumours become resistant and afflicted women succumb to breast cancer. In the proposed concept, when the tumour region is loaded with boron-10 it is irradiated with neutrons (treatment used for head and neck cancers, melanoma and glioblastoma for over 40 years in Japan and Europe). The irradiation process takes less than an hour producing minimal side effects. This paper summarizes our recent theoretical assessments of radiation binary targeted therapy for HER-2 positive breast cancers on: the effective drug delivery mechanism, the numerical model to evaluate the targeted radiation delivery and the survey study to find the neutron facility in the world that might be capable of producing the radiation effect as needed. A novel method of drug delivery utilizing Trastuzumab is described, followed by the description of a computational Monte Carlo based breast model used to determine radiation dose distributions. The total flux and neutron energy spectra of five currently available neutron irradiation treatment facilities are examined for this application. The tumour boron concentrations and tumour to healthy tissue concentration ratios required to deliver 50 Gy-Eq to the tumour without exceeding 18 Gy-Eq in the skin are determined, as well as the associated therapeutic ratios. Discussion is provided to address the future research direction for assessing the feasibility of the proposed concept.

MCNP5 evaluation of dose dissipation in tissue-like media exposed to low-energy monoenergetic X-ray microbeam.

Following a significant increase in the number of facilities in the world having and developing low- and high-linear energy transfer (LET) microbeams for experimental radiobiological studies, it is useful and demanding to establish reliable computational models to analyze such experiments. This paper summarizes initial MCNP5 calculations of the basic parameters needed to study X-ray microbeam penetration, dose deposition and dose spatial dissipation in tissue-like media of micro and macro scales. The presented models can be used to predict doses delivered to neighboring cells and analyze the cause of bystander cell deaths. In the case of low-LET radiation, dose distribution is more homogenized when compared to high-LET that deposits almost all of its energy in the cell hit by radiation. Results are presented for a microbeam of monoenergetic soft (2-10 keV) X-rays for two different micro-models: (a) single-cells of homogeneous and uniform chemical compositions, and (b) single-cells of heterogeneous structures (nucleus and cytoplasm) with different chemical compositions. In both numerical models, only one cell is irradiated and the electron and X-ray doses in all cells are recorded. It was found that surrounding cells receive approximately five orders of magnitude less dose than the target cell in the homogenized cell model. The more detailed, heterogeneous model showed that the nucleus of the target cell receives more than 95% of the dose delivered to the entire cell, while neighboring cell nuclei receive approximately 65% of their total cell dose. Results of the macroscopic behavior of a soft X-ray microbeam using a cylindrical phantom 5 cm tall and 1 cm in diameter are also presented. Three-dimensional dose profiles indicate the spatial dose dissipation. For example, a 10 keV X-ray microbeam dose scatters to a negligible level at 0.3 cm radially from the center while it reaches an axial depth of 2 cm.

Computational assessment of improved cell-kill by gadolinium-supplemented boron neutron capture therapy.

Potential improvement in neutron capture therapy (NCT) by utilizing both 157Gd and 10B is assessed considering two parameters calculated in transport models in MCNP4B, the dose to quiescent cells and the therapeutic ratio. Improved sterilization of quiescent or more generally non-uptaking cells is demonstrated with the addition of 157Gd to conventional 10B loading. The improved dose delivery to non-uptaking cells from concurrent administration of 157Gd and 10B is weighed against a second index, degradation in the therapeutic ratio resulting from the longer interaction lengths of the 157Gd capture products. Optimal concentrations of 157Gd are determined considering varying assumptions for boron uptake levels and selectivity. By analysing the dosimetry results of varying 157Gd concentrations applied concurrently with BPA-delivered boron in NCT, this work seeks to determine a balance between the high tumour-specific dose provided by BPA and the high dose to quiescent cells provided by potential gadolinium agents. Depending upon the assumptions for drug specificity, tumour size and fraction of quiescent cells, NCT with low levels of 157Gd (125 microg g(-1)) supplementing 10B loadings was shown to be superior to treatments applying 10B alone.